This randomized phase III trial studies tamoxifen citrate or letrozole together with bevacizumab to see how well it works compared with tamoxifen citrate or letrozole alone in treating women with stage III or stage IV breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate* or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Monoclonal antibodies, such as bevacizumab, may help control breast cancer by stopping the growth of blood vessels to the tumor. It is not yet known whether giving hormone therapy is more effective with or without bevacizumab in treating advanced breast cancer.

Graded using the NCI CTCAE version 4.0. Tabulated by type, grade, and arm.

Time-to-treatment failure [ Time Frame: From randomization until first disease progression, early termination of protocol therapy due to toxicity or withdrawn consent, or beginning non-protocol therapy, whichever occurs first, assessed up to 5 years ] [ Designated as safety issue: No ]

Defined by RECIST criteria. The proportional hazards model will be used to compare the arms on time-to-treatment-failure.

Duration of tumor response [ Time Frame: From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years ] [ Designated as safety issue: No ]

Defined by RECIST criteria.

Overall survival (OS) [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]

Compared with a Kaplan-Meier analysis. 90% confidence interval will be calculated.

Probability of surviving until 36 months [ Time Frame: At 36 months ] [ Designated as safety issue: No ]

Descriptive statistics and proportional hazards regression modeling will be examined. A variety of functional forms, including untransformed values, logarithms, and cutpoints will be used, as will regression trees and loess plots within test/validation samples to explore cutpoints.

A multivariate proportional hazards model that relates various functional forms of CTC and CEC levels to the hazard of progression. The mixed linear model will be used to test for arm differences in changes in CTCs and CECs across time.

The association of PIK3CA with dichotomous markers will be assessed with contingency tables and the chi-square test. A variety of functional forms will be considered through the use of cutpoints, loess plots and restricted cubic splines.

The association of PIK3CA with dichotomous markers will be assessed with contingency tables and the chi-square test. A variety of functional forms will be considered through the use of cutpoints, loess plots and restricted cubic splines.

The association of PIK3CA with continuous markers such as VEGF will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

The association of PIK3CA with continuous markers will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

The association of PIK3CA with continuous markers will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

The association of PIK3CA with continuous markers will be assessed by using the logistic regression model to examine the functional form of the association. A variety of functional forms will be examined through the use of cutpoints, loess plots and restricted cubic splines.

Improvement in PFS due to bevacizumab depends on the VEGF gene [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]

This will be investigated in the framework of a two-way multiplicative log-linear Cox model with factors drug (P=control or B=bevacizumab) and VEGF gene (1=CT/TT or 2=CC).

Identify SNPs associated with PFS [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]

Logistic regression models and conditional inference trees (or more generally conditional random forests) will be used to construct multi-variable models based on the SNPs identified as interesting. This model also allows for inclusion of other potentially relevant clinical demographic variables.

Association between each CNV marker and the clinical adverse event (AE) endpoint [ Time Frame: Assessed up to 3 years ] [ Designated as safety issue: No ]

This will be assessed using the Wilcoxon two-sample test. Regression methods, as in the case of the SNP markers, will be employed to construct multivariable models based on the CVN markers.

Associations between the occurrence of grade 3, 4, or 5 toxicity and clinical factors [ Time Frame: Baseline to 3 years ] [ Designated as safety issue: No ]

To account for multiple comparisons in the primary objective, a Bonferroni correction will be applied to a two-sided Type I error of 0.05. For the continuous factors (Medical Outcome Study [MOS] Physical Functioning, Karnofsky Performance Status Rated Healthcare Professional, Timed "Up and Go", Older American Resources and Services [OARS] Physical Health Section), logistic regression will be used to determine the odds ratio of toxicity.

Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: tamoxifen citrate

Given PO

Other Names:

Nolvadex

TAM

tamoxifen

TMX

Drug: letrozole

Given PO

Other Names:

CGS 20267

Femara

LTZ

Biological: bevacizumab

Given IV

Other Names:

anti-VEGF humanized monoclonal antibody

anti-VEGF monoclonal antibody

Avastin

rhuMAb VEGF

Other: laboratory biomarker analysis

Correlative studies

Other: questionnaire administration

Ancillary studies

Active Comparator: Arm II (endocrine therapy)

Patients receive endocrine therapy* (tamoxifen citrate* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Patients may not have a "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse

Tumors (from either primary or metastatic sites) must express estrogen receptor (ER) and/or progesterone receptor (PgR) in >= 1% of cells will be considered positive

Postmenopausal women are eligible for this trial; before study registration, menopausal status must be defined according to the criteria below:

Age >= 55 years and one year or more of amenorrhea

Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml

For women age < 55 with prior hysterectomy but intact ovaries, with an estradiol assay < 20 pg/ml

Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration)

Premenopausal women who do not meet the postmenopausal criteria above are also eligible, but are required to undergo ovarian suppression; this can be initiated any time prior to or on day 1 of protocol therapy, regardless of chosen endocrine therapy, and will continue for the duration of protocol therapy

Must have measurable or nonmeasurable disease by RECIST criteria, with radiologic scans within 28 days of study registration

Measurable disease: lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2.0 cm with conventional techniques or as >= 1.0 cm with spiral computed tomography (CT) scan

Nonmeasurable disease: all other lesions, including small lesions (longest diameter < 2.0 cm with conventional techniques or < 1.0 cm with spiral CT scan) and truly nonmeasurable lesions, including any of the following:

Bone lesions

Leptomeningeal disease

Ascites

Pleural/pericardial effusion

Inflammatory breast disease

Abdominal masses that are not confirmed and followed by imaging techniques

Cystic lesions

Prior endocrine therapy is not required

Prior endocrine therapy in the metastatic setting is not permitted (unless tamoxifen or an aromatase inhibitor was initiated within 4 weeks prior to registration to facilitate enrollment of patients who recently started first-line endocrine therapy for metastatic breast cancer); if prior letrozole therapy was initiated within the past 4 weeks, the patients should remain on letrozole as the study therapy; patients who began therapy with tamoxifen, anastrozole or exemestane must switch to letrozole to be eligible to participate in this study

Prior endocrine therapy in the adjuvant setting is permitted; there is no time restriction for how long the patient must be on the adjuvant endocrine therapy, nor is there a time restriction for how long the patient needs to be off prior adjuvant endocrine therapy before beginning protocol therapy on 40503

Prior treatment with ovarian suppression is allowed in either the adjuvant or metastatic setting; if medical ovarian suppression is being administered it can be initiated any time prior to or at the start of protocol therapy, and continued throughout the duration of the trial; surgical castration with bilateral oophorectomy must be performed at least 28 days prior to study registration (due to concerns of poor wound healing on bevacizumab)

Patients may not have received any prior anti-VEGF or VEGF receptor (VEGFR) tyrosine kinase inhibitor therapy

Prior radiotherapy must have been completed and all toxicities resolved at least two weeks prior to registration

Chemotherapy in the adjuvant or neoadjuvant setting is permitted; at least twelve months prior to registration must have elapsed since the completion of adjuvant or neoadjuvant chemotherapy and all toxicities must have resolved; taxane-related neurotoxicity must have resolved to sensory grade < 2 and no motor neuropathy of any grade is allowed

Patients may have received one prior chemotherapy regimen for metastatic disease; the final dose of prior chemotherapy must have been administered at least 3 weeks prior to study registration

Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines

Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study registration, and must have fully recovered from any such procedure

Patients must not have anticipation of need for major surgical procedure during the course of the study

Patients must not have had a core biopsy or other minor surgical procedure, within 7 days prior to study registration; placement of a vascular access device is allowed within 7 days of registration

Patients must not have a history of abdominal fistula, or intra-abdominal abscess within 6 months prior to study registration

Patients with a history of gastrointestinal (GI) perforation within 12 months prior to registration are not eligible

Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within 6 months prior to registration are not eligible

Patients must not have clinically significant cardiovascular disease that includes the following:

Full dose anticoagulation therapy is allowed for the treatment of prior conditions such as venous thrombosis or atrial fibrillation, but not for the treatment of prior arterial thrombotic events; patients on full dose anticoagulants must be on a stable dose of warfarin and have an in-range international normalized ratio (INR) (usually between 2 and 3) or be on a stable dose of low-molecular weight (LMW) heparin; patients receiving antiplatelet agents are eligible, as are patients on daily prophylactic aspirin or anticoagulation for atrial fibrillation

Patients may not have a history of stroke or transient ischemic attack within 6 months prior to study registration

Patients with a history of seizures must be well controlled with standard medication

Patients must not have known central nervous system (CNS) metastases or leptomeningeal disease (screening with brain imaging is not required for asymptomatic patients)

In aromatase inhibitor (AI)-treated patients: no known allergies to imidazole drugs, (e.g. clotrimazole, ketoconazole, miconazole, econazole, sulconazole, ticonazole, or terconazole) or compounds structurally similar to bevacizumab

In tamoxifen treated patients: no known allergies to selective estrogen receptor modulators (e.g. tamoxifen, raloxifene or toremilfene) or compounds structurally similar to bevacizumab; for patients enrolled after Update #5, endocrine therapy will consist of letrozole only and this criterion will no longer apply

All patients who are premenopausal (if not already receiving ovarian suppression therapy/surgical oophorectomy) must have a negative beta-human chorionic gonadotropin (beta-Hcg) prior to starting on study treatment; patients may not be pregnant or nursing at any time during the study; ovarian suppression is required in women of childbearing potential by the start of protocol therapy, and will continue for the duration of protocol therapy

Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr, or UPC ratio < 1 to allow participation in the study

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Please refer to this study by its ClinicalTrials.gov identifier: NCT00601900